The Project will continue to pursue the important issue of defining the role of endocannabinoids in memory and related cognitive processes as determined by the effects on information encoding in hippocampal neurons. The Proposal describes studies that address this question from two different strategic but convergent technologies. Experiments conducted in vitro in hippocampal slices are described that will continue to delineate the minimal, synapse mediated, depolarizing conditions required to release endocannabinoids from hippocampal neurons that act in a retrograde manner to suppress release of inhibitory (DSI) or excitatory transmitters (DSE) onto those same cells. These findings will be related directly to intracellular calcium dynamics as an intermediary step required for release by depolarizing influences. A second complementary strategy has been developed on the basis of our recent discovery that endocannabinoids are involved in the encoding of information by ensembles of hippocampal neurons during performance of a well characterized short-term memory task in rats. This second approach utilizes the fact that hippocampal ensembles have distinct firing patterns which are altered when endocannabinoids are released on some occasions during performance of the task. Experiments will utilize a unique closed loop testing paradigm that ties hippocampal encoding of trial specific information to performance as a function of the length of delay on the same DNMS trial. The influence of released endocannabinoids on this encoding process and its behavioral consequences will be examined using this paradigm in association with pharmacological manipulation of processes involved in endocannabinoid release and CB1 receptor mediated cellular processes. The two strategies will be combined to fully disclose the nature of endocannabinoid actions in hippocampus by employing recently developed patterned multisite electrostimulation that mimics endocannabinoid release in vitro to alter performance in the same manner as when endocannabinoids are released spontaneously in the behaving animal.Relevance: Because cannabinoids are one of the most abused substances in modern society, an understanding of how they produce their well-known memory impairments that occur during recreational and addictive use is of paramount importance to the eventual control of this debilitating influence. The outcomes of these studies will define not only what type of neural processes are susceptible to disruption by cannabinoid use, but also when the encoding of information by those processes is susceptible to such influence.